BACKGROUND A hallmark of human cancer, particularly solid tumor, is genomic instability. Through a synthetic lethal screen with the Ras oncogene we have found that Ras mutant cancer cells exhibit increase mitotic stress and are more dependent on the proper function of a number of mitotic genes. PURPOSE To study the effect of Ras mutation in mitosis and in chromosomal segregation. To understand the mechanisms by which mutant Ras affects the mitotic machinery. SIGNIFICANT MATERIALS AND METHODS We will use KRAS WT and mutant isogenic cells as well as cancer cell lines that are either dependent or independent of KRAS to investigate their response to perturbation of mitotic progression. FY2011 ACCOMPLISHMENT In the past year we have identified a novel gene that 1) show synthetic lethality with Ras mutation and 2) is required for chromosome congression in mitosis. The expression of this gene is associated with aggressive colorectal cancer (CRC) and poor prognosis in CRC patients with KRAS mutations. We are currently invstigating the mechanisms by which this gene regulates mitosis and genomic stability.